DEVELOPMENTAL THERAPEUTICS (DT) RESEARCH PROGRAM PROJECT SUMMARY/ABSTRACT The Developmental Therapeutics (DT) Research Program develops and evaluates novel therapeutics and combinations that: 1) overcome drug resistance of cancer cells mediated by a spectrum of genetic and epigenetic mechanisms; 2) inhibit growth and drug-resistant pathways of cancer; and 3) utilize novel immune checkpoint therapeutics to increase the proportion of cancer patients who benefit. The overall approach of the DT Program is to leverage the creativity and expertise of basic scientists in the Case Comprehensive Cancer Center (Case CCC) Programs by analyzing new agents for specific validated molecular targets and new therapeutic compounds for preclinical and clinical validation in early-phase clinical trials. DT members guide their development, and convey clinical samples back to laboratory investigators to drive further discovery. This bidirectional interchange enables DT's continued role as a major convener of new therapeutic concepts for the Center?s Programs. The program is organized around 3 scientific aims: (1) Interrogate cancer pathways to develop new efficacious therapeutics; (2) Implement early-phase clinical trials around novel pathway targets, new agents and combinatorial approaches; and (3) Implement early-phase trials around novel approaches to cancer immunotherapies, to widen their activity spectra. These aims reflect major working groups and initiatives that coalesces program members with other cancer center investigators through inter-programmatic collaborations that result in preclinical and clinical research efforts, grants, and trial protocols. Extensive use of an array of shared resources, in particular Translational, Cytometry, Imaging, Proteomics, and Drug Discovery facilitate all aspects of member discoveries. Under the leadership of Yogen Saunthararajah (Co-Leader) and John Letterio (Co-Leader) the DT Program has 52 members including 18 full, 5 associate and 29 clinical members representing 21 different departments across the consortium. Members are funded by a total of $12.5M in research grant funding (annual direct costs), of which $5.1M is peer-reviewed and $2.9M is NCI-funded. Between 2012 and 2016, DT program members published 1,012 publications. Cancer and program related publications included 35% inter- programmatic, 25% intra-programmatic, 14% inter- and intra-programmatic and 10% that involved collaborations with another Cancer Center. This highly effective Program has made major practice-changing contributions benefiting cancer patients. Examples include: discoveries of first-in-class compounds (SMARCA5 inhibitor, PP2A activator, malate dehydrogenase inhibitor, base excision repair target with methoxyamine); discoveries targeting EGFR resistance, inhibition of uracil glycosylase and the inhibition of the BH4 domain of Bcl-2; analysis into the genetic markers of resistance to radiation; and identification of several small cell lung cancer genetic subsets. !